Neuronal Ca2+ signaling through endoplasmic reticulum (ER)-localized inositol trisphosphate (IP3R) and ryanodine receptors (RyR) must be tightly regulated to maintain cell viability, both acutely and over the lifetime of an organism. Exaggerated ER Ca2+ release (up to 4-fold) has been associated with Alzheimer disease (AD) mutations expressed in cell cultures and young mice, but little is known of Ca2+ dysregulations during the normal and pathological aging processes using adult and aged models. The hypothesis is that early intracellular Ca2+ dysregulation represents a unique 'calcium-opathy'that contributes to later progression of AD, and is not an accelerated component of normal aging. Aim I of this study will determine and differentiate the distinct roles of neuronal IP3 and Ry Ca2+ channels in a non-transgenic control mouse and the 3xTg-AD mouse model of AD. Aim II will analyze the effects of age and AD mutations on the magnitude of the exaggerated ER Ca2+ signals, determine downstream effects on electrophysiological membrane properties and synaptic activity, and parse the contributions of PS1, APP, and tau mutations by comparing 3xTg-AD, APP/Tau, PS1KI and NonTg control mice. Aim III will seek to pharmacologically reverse the exaggerated ER Ca2+ release in the 3xTg-AD neurons and measure effects on amyloid plaque deposition. Likewise, amyloid plaques will be cleared in older 3xTg-AD mice using immunotherapy techniques, and establish if there is a functional relationship between the early Ca2+ dysregulation and AD histopathology. These studies combine electrophysiological recording in brain slices, 2-photon Ca2+ imaging, and flash photolysis of caged compounds from control (non-transgenic), 3xTg-AD, APP/Tau and PS1KI mice at young, adult, and old ages. Immunohistochemical techniques will be used to map and quantify changes in the expression of IP3R and RyR subtypes, and extent of AD histopathology. These findings will elucidate intracellular signaling changes and downstream effects on neuronal physiology that occur both in normal aging, and in neurodegenerative disorders such as AD. PUBLIC HEALTH RELEVANCE: The objective of this study is to determine the functional relationship between early changes in neuronal Ca2+ signaling, and later pathophysiology associated with aging and Alzheimer's disease (AD). The results of this study will have scientific and clinical relevance by differentiating between neuronal signaling changes associated with normal aging and those associated with AD pathogenesis. Benefits to public health include the prospect for earlier AD diagnosis and novel therapeutic intervention, long before the onset of cognitive decline and irreversible histopathology.